Project Summary A major issue of ignorance in sensory processing is how the brain develops its remarkable ability to use its senses synergistically, a critical requirement for normal perception. We do know however, that acquiring this capability is a protracted postnatal process, and the ability to use visual and auditory information cooperatively must be learned. This process is best understood in terms of the detection and orientation behaviors mediated by the superior colliculus (SC), a midbrain structure well-endowed with multisensory neurons. After extensive visual-auditory experience, animals show enhanced visual-auditory detection and localization behaviors. Their multisensory SC neurons show similar changes ? now integrating their different sensory inputs to enhance their response and the physiological salience of the initiating events. The brain has come to treat these cross- modal stimuli as a coherent whole rather than as a set of competitive or unrelated cues. These changes are not seen in animals reared in darkness or with masking noise, and chemical lesions preferentially eliminating SC multisensory neurons eliminate the enhanced multisensory detection and orientation behaviors without disrupting responses to their individual component cues. Interestingly, this integrative capacity and its performance benefits in detecting and orienting to external events can be acquired in dark-reared and noise- reared animals by giving them appropriate experience later in life. But, the conceptual and practical use of this information is limited by a poor understanding of the factors underlying its acquisition and operation. We suggest the acquisition of this SC capacity does not depend on forming generic associations between the sensory modalities as is widely believed. Rather, it involves a far more sophisticated form of statistical learning in which the probability that any set of cross-modal inputs derive from the same event is encoded. This information is then used by the circuit to determine how it will later respond to such events. But to be effective in this regard, those cross-modal inputs must access the SC through unisensory projections from association cortex (and be filtered by the SC?s inherent biases). We posit that this natural process can be reproduced artificially by inducing covariant activation of these converging cortico-SC afferents - in the absence of external cues, and without any of the reinforcement contingencies or cognitive factors normally associated with overt behavior. Finally, we hypothesize that NMDA receptors provide the crucial mechanistic basis for encoding this experience by initiating Hebbian-like learning algorithms. The end result is a multisensory system that is extremely sensitive to the particular cross-modal stimulus configurations that were learned to belong to the same events. This gives them preferential access to the neural machinery that will still further enhance their physiological salience and their ability to elicit SC-mediated behavior, ensuring that the system is adapted to the environment in which it was formed, and in which it will likely be used.